Optimization of the first small-molecule relaxin/insulin-like family peptide receptor (RXFP1) agonists: Activation results in an antifibrotic gene expression profile

  • Eur J Med Chem. 2018 Aug 5;156:79-92. doi: 10.1016/j.ejmech.2018.06.008.
Kenneth J Wilson  1 ,  Jingbo Xiao  1 ,  Catherine Z Chen  1 ,  Zaohua Huang  2 ,  Irina U Agoulnik  2 ,  Marc Ferrer  1 ,  Noel Southall  1 ,  Xin Hu  1 ,  Wei Zheng  1 ,  Xin Xu  1 ,  Amy Wang  1 ,  Courtney Myhr  2 ,  Elena Barnaeva  1 ,  Emmett R George  1 ,  Alexander I Agoulnik  2 ,  Juan J Marugan  3
Affiliations
  • 1. NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
  • 2. Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, HLSI 419B, Miami, FL, 33199, USA.
  • 3. NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA. Electronic address: [email protected].
PMID: 30006176 DOI: 10.1016/j.ejmech.2018.06.008
Abstract

A dose responsive quantitative high throughput screen (qHTS) of >350,000 compounds against a human relaxin/insulin-like family peptide receptor (RXFP1) transfected HEK293 cell line identified 2-acetamido-N-phenylbenzamides 1 and 3 with modest agonist activity. An extensive structure-activity study has been undertaken to optimize the potency, efficacy, and physical properties of the series, resulting in the identification of compound 65 (ML-290), which has excellent in vivo PK properties with high levels of systemic exposure. This series, exemplified by 65, has produced first-in-class small-molecule agonists of RXFP1 and is a potent activator of anti-fibrotic genes.

Keywords
2-Acetamido-N-Phenylbenzamide; Antifibrotic; G-protein coupled receptor; Relaxin.
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